PHARMACEUTICAL FORMULATION FOR DELIVERY OF RECEPTOR TYROSINE KINASE INHIBITING (RTKi) COMPOUNDS TO THE EYE

Abstract

The present invention relates to development of efficacious pharmaceutical compositions comprising a poorly water soluble active compound in a therapeutically effective amount and a co-solvent in a suitable amount to treat or prevent diseases due to ocular neovascularization and enhanced vascular permeability. In preferred aspects the composition is in the form of a gel.

Description

[0001] This application claims priority to U.S. provisional application Ser. No. 60 / 753,749 filed Dec. 23, 2005.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to compositions and methods useful for treating pathological states that arise or are exacerbated by ocular angiogenesis and vascular leakage such as AMD, DR, diabetic macular edema etc., and more specifically, to compositions containing at least one anti-angiogenic agent, anti-inflammatory agent, or anti-vascular permeability agent for use in treating angiogenic ocular disorders. [0004] 2. Description of the Related Art [0005] Abnormal neovascularization or angiogenesis and enhanced vascular permeability are major causes for many ocular disorders including age-related macular degeneration (AMD), retinopathy of prematurity (ROP), ischemic retinal vein occlusions and diabetic retinopathy (DR). AMD and DR are among the most common cause of severe, irreversible vision loss. In th...

AI Technical Summary

Benefits of technology

[0018] One advantage of the present invention is that the PEG water-miscible erodible gel formulation can dissolve in water at a controlled rate, while the active agent in the formulation forms a colloidal dispersion at the site of action. This suggests that the PEG water-soluble carrier can be eliminated from the eye. At the end of use, the system does not need to be retrieved. This is a significant improvement over other existing forms of delivering active agents to the eye of a patient because it allows for fewer invasive procedures while providing superior treatment of the neovascularization, vascular permeability or other ocular disorder. The erosion can be controlled by the ratio of low and high molecular weights of PEGs. The desirable bioavailability can be achieved by controlling the rate of erosion and the rate of dissolution of the colloidal particles which is formed in-situ.

[0019] It is contemplated that any active agent that is poorly water soluble may be included in the compositions of the present invention. For example, anti-angiogenic agents, anti-inflammatory agents, or anti-vascular permeability agents are useful in the compositions of the invention.

[0020] Preferred anti-angiogenic agents include, but are not limited to, receptor tyrosine kinase inhibitors (RTKi), in particular, those having a multi-targeted receptor profile such as that described in further detail herein; angiostatic cortisenes; MMP inhibitors; integrin inhibitors; PDGF antagonists; antiproliferatives; HIF-1 inhibitors; fibroblast growth factor inhibitors; epidermal growth factor inhibitors; TIMP inhibitors; insulin-like growth factor inhibitors; TNF inhibitors; antisense oligonucleotides; etc. and prodrugs of any of the aforementioned agents. The preferred anti-angiogenic agent for use in the present invention is a multi-targeted receptor tyrosine kinase inhibitor (RTKi). Most preferred are RTKi's with multi-target binding profiles, such as N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea, having the binding profile substantially similar to that listed in Table 1. Additional multi-targeted receptor tyrosine kinase inhibitors contemplated for use in the compositions of the present invention are described in U.S. Application Serial No. 2004/0235892, incorporated herein by reference. As used herein, the term “multi-targeted receptor tyrosine kinase inhibitor” refers to a compound having a receptor binding profile exhibiting selectivity for multiple receptors shown to be important in angiogenesis, such as the profile shown in Table 1, and described in co-pending U.S. application serial number 2006/0189608, incorporated herein by reference. Most preferably, the compounds for use in the formulations of the present invention will have a receptor binding profile of KDR (VEGFR2), Tie-2 and PDGFR. TABLE 1Kinase Selectivity Profile of a RTK InhibitorKDRFLT1FLT4PDGFRCSF1RKITFLT3TIE2FGFREGFRSRC43190663144170>12,500&g

Problems solved by technology

AMD and DR are among the most common cause of severe, irreversible vision loss.

While there appear to be many stimuli for retinal neovascularization, including tissue hypoxia, inflammatory cell infiltration and penetration barrier breakdown, all increase the local concentration of cytokines (VEGF, PDGF, FGF, TNF, IGF etc.), integrins and proteinases resulting in the formation of new vessels, which then disrupt the organizational structure of the neural retina or break through the inner limiting membranes into the vitreous.

Elevated cytokine levels can also disrupt endothelial cell tight junctions, leading to an incre